Research in the pulmonary pathology laboratory has been focused upon the basic biological mechanisms through which inhaled particles cause lung disease. We have developed models of asbestosis and silicosis using rats and mice and have shown that the disease process is initiated at junctions of bronchioles and alveolar ducts. One hour of exposure to chrysotile asbestos is sufficient to cause progressive fibrogenesis at alveolar duct bifurcations. The process is initiated by a complement-dependent chemoattraction of lung macrophages to the sites of particle deposition. The central working hypothesis in our laboratory is that these macrophages synthesize and secrete an array of products which mediate the pathogenesis of lung fibrosis. Studies over the past years have shown that macrophages produce a wide array of arachidonic acid metabolites. These are potent inducers of inflammation and cell migration. Now we are focusing upon a group of cell-derived proteins collectively termed 'growth factors'. The growth factor which is the most potent inducer of mesenchymal cell (e.g. fibroblasts and smooth muscle cells) proliferation is platelet-derived growth factor (PDGF). The most potent stimulator of extracellular matrix production by mesenchymal cells is transforming growth factor beta (TGFbeta). We have shown that lung macrophages secrete generous quantities of both of these factors. Thus, we postulate that inhalation of toxic particles activates populations of lung macrophages which produce PDGF and TGFbeta, the factors which could mediate the consequent fibrogenic response. To test this hypothesis, an extended series of experiments is ongoing to understand the biology, biochemistry and molecular nature of the growth factors in asbestos exposed animals and their cells. Most recently we have shown that alpha-macroglobulin (alpha-M), a high molecular weight antiprotease, is secreted by lung macrophages and serves as a specific binding protein for the macrophage-derived PDGF. Then we showed that the alpha-M enhances, by more than 100%, the ability of PDGF to stimulate the proliferation of rat lung fibroblasts. Efforts to block the biological activity of the growth factors with appropriate antibodies in vivo have just been initiated.